The invention relates to a topical pharmaceutical composition comprising as pharmaceutical active agent a retinoid in a physiologically acceptable medium, to the method for the preparation thereof and to the use thereof in dermatology.
In the field of dermatology and of the formulation of pharmaceutical compositions, those skilled in the art are led to use compositions that must be physically and chemically stable. They must also allow the release of the active agent and promote its penetration into the skin layers in order to improve its efficacy.
The horny layer or stratum corneum is the most superficial part of the epidermis. Conventionally likened to a wall of “bricks and mortar”, it consists of dead cells, corneocytes, embedded in inter-corneocyte lipids. The stratum corneum lies on the epidermis which is the first viable layer of the skin. It contains numerous cell types and is avascular. Finally, the dermis consists of a small number of cells, numerous proteins which provide support for the tissue, and a vascular network. While the stratum corneum is principally lipophilic in nature owing to the presence of the inter-corneocyte lipids, the epidermis and the dermis are principally hydrophilic in nature, the presence of vessels in the dermis additionally providing clearance of this compartment.
It is commonly accepted that the mechanisms of cutaneous penetration and permeation are dependent, on the one hand, on the coefficients of partition of the compounds between the vehicle applied and the various compartments of the skin (stratum corneum, epidermis then vascular dermis) and, on the other hand, on the coefficient of diffusion of these compounds in each layer of the skin. Depending on their physicochemical characteristics, in particular their lipophilic nature, certain compounds exhibit a high affinity and a high coefficient of diffusion in the stratum; they are therefore stored in the stratum, and to a lesser extent in the epidermis. On the other hand, their partition in the dermis, which is vascularized, and which is more hydrophilic in nature than the epidermis or the stratum, will be low. In this case, the upper layers of the skin, and in particular the stratum, then constitute an actual reservoir for the accumulation of the pharmaceutical active agent. Typically, the penetration kinetics of such compounds exhibit, over time, an increase in the amount of active agent in the stratum, and to a lesser extent in the epidermis, followed by a plateau during which this amount no longer varies. The state of equilibrium between the penetration of the active agent into the compartment and its clearance is then reached.
In certain cases, it is important to be able to modulate these typical kinetics in such a way that the pharmaceutical active agent can penetrate weakly into the skin in a prolonged and controlled manner. This type of penetration and accumulation in the skin can then be similar to zero order kinetics, with reference to the zero order linear kinetics of diffusion and transcutaneous permeation observed for certain pharmaceutical preparations applied to a membrane or to skin.
The active molecules, the passage of which to their target is sought, are rarely isolated; they are usually in a more or less complex formulation which, as appropriate, may be a cream, an ointment, a lotion, a powder or a gel.
After the phase of contact between the molecule and the surface of the skin, the active substance will have to leave its vehicle in order to penetrate into the horny layer, with more or less ease.
Generally, topical pharmaceutical compositions such as gels, creams, lotions or solutions release the active ingredient(s) by diffusion directly proportional to the concentration gradient in the composition.
In other words, after application to the skin, the active ingredient(s) is (are) released relatively immediately and then the release kinetics tend toward zero to obtain a plateau. The active ingredient(s) is (are) then no longer absorbed on the skin.
In order to obtain release kinetics independent of the concentration gradient, there are several types of topical formulations, such as:                the formulation of supersaturated solutions, i.e. compositions in which the active ingredient(s) is (are) in very concentrated solution,        the production of patches in which the release of the active ingredient(s) is controlled by a membrane, which is permeable and generally adhesive, directly in contact with the skin.        
Supersaturated solutions are very often unstable and do not make it possible to obtain good physical stability of the composition which may be a gel, a cream, a lotion or an ointment. Patches are, on the other hand, more stable, but have the drawback of a more complex processing with an application surface area limited by the size of the patch.